Polygenic Risk Scores: The Next Step for Improved Risk Stratification in Coronary Artery Disease? / Escores de Risco Poligênico: O Próximo Passo para Melhorar a Estratificação de Risco na Doença Arterial Coronariana?

Despite significant advances in the management of coronary artery disease (CAD) and reductions in annual mortality rates in recent decades, this disease remains the leading cause of death worldwide. Consequently, there is an ongoing need for efforts to address this situation. Current clinical algorithms to identify at-risk patients are particularly inaccurate in moderate-risk individuals. For this reason, the need for ancillary tests has been suggested, including predictive genetic screening. As genetic studies rapidly expand and genomic data becomes more accessible, numerous genetic risk scores have been proposed to identify and evaluate an individual's susceptibility to developing diseases, including CAD. The field of genetics has indeed made substantial contributions to risk prediction, particularly in cases where children have parents with premature CAD, resulting in an increased risk of up to 75%. The polygenic risk scores (PRSs) have emerged as a potentially valuable tool for understanding and stratifying an individual's genetic risk. The PRS is calculated as a weighted sum of single-nucleotide variants present throughout the human genome, identifiable through genome-wide association studies, and associated with various cardiometabolic diseases. The use of PRSs holds promise, as it enables the development of personalized strategies for preventing or diagnosing specific pathologies early. Furthermore, it can complement existing clinical scores, increasing the accuracy of individual risk prediction. Consequently, the application of PRSs has the potential to impact the costs and adverse outcomes associated with CAD positively. This narrative review provides an overview of the role of PRSs in the context of CAD.

Apesar dos avanços significativos no tratamento da doença arterial coronariana (DAC) e das reduções nas taxas de mortalidade anuais nas últimas décadas, a DAC continua sendo a principal causa de morte no mundo. Consequentemente, há uma necessidade contínua de esforços para abordar essa situação. Os algoritmos clínicos atuais para identificar pacientes em risco são particularmente imprecisos para indivíduos de risco moderado. Por esse motivo, foi sugerido que são necessários testes auxiliares, incluindo triagem genética preditiva. À medida que os estudos genéticos se expandem rapidamente e os dados genômicos se tornam mais acessíveis, diversos escores de risco genético têm sido propostos para identificar e avaliar a suscetibilidade de um indivíduo ao desenvolvimento de doenças, incluindo a DAC. De fato, o campo da genética tem contribuído substancialmente para a previsão de risco, particularmente nos casos em que as crianças têm genitores com DAC prematura, resultando em um risco aumentado de até 75%. Os escores de risco poligênico (PRSs, do inglês polygenic risk scores) surgiram como uma ferramenta potencialmente valiosa para compreender e estratificar o risco genético de um indivíduo. O PRS é calculado como uma soma ponderada de variantes de nucleotídeo único presentes em todo o genoma humano, identificáveis por meio de estudos de associação genômica ampla, e associadas a várias doenças cardiometabólicas. O uso dos PRSs é promissor, pois permite o desenvolvimento de estratégias personalizadas para prevenir ou diagnosticar patologias específicas de forma precoce. Ademais, seu uso é capaz de complementar os escores clínicos existentes, aumentando a precisão da previsão de risco individual. Consequentemente, a aplicação dos PRSs tem o potencial de impactar positivamente os custos e os desfechos adversos associados à DAC. A presente revisão narrativa oferece uma visão ampla do papel dos PRSs no contexto da DAC.

The association of ghrelin rs26311 and rs27647 polymorphisms and mRNA expression with preeclampsia susceptibility and severity-A case-control study.

OBJECTIVE: Ghrelin is an adipokine the placenta generates to control the maternal metabolic adaptation to pregnancy. It causes different pregnancy complications like preeclampsia (PE). Therefore, the aim of this study was to assess the association between ghrelin mRNA expression and rs26311 and rs27647 polymorphisms and PE development. METHODS: In total, 156 PE women (including 97 patients with mild PE and 59 patients with severe PE) and 152 healthy controls were recruited in this case-control study during 2019-2020. All participants with other diseases have been excluded from both groups. The ghrelin expression was analyzed with real-time PCR, and ghrelin variants were examined using the RFLP-PCR method. RESULTS: The maternal and placental ghrelin rs27647 and rs26311 variants were unrelated to PE susceptibility. Haplotype analyses showed no significant difference between the four haplotypes and PE. No relationship was revealed between rs27647 polymorphism and severe PE. However, the results indicated a relationship between rs27647 and severe PE compared to mild PE and controls. Therefore, the rs27647 variant was associated with severe PE compared to mild PE in codominant, recessive, and log-additive models and controls in codominant, dominant, recessive, and log-additive models. The placental ghrelin mRNA expression declined in PE women compared to controls (0.67-fold), but the difference was insignificant (p=0.263). No significant difference was found between various genotypes of rs27647 and rs26311 polymorphisms concerning ghrelin mRNA expression. CONCLUSION: The maternal and placental ghrelin polymorphisms, rs27647 and rs26311, showed no effect on PE. However, the rs27647 variant was associated with severe PE.

Mitochondrial genome variants associated with amyotrophic lateral sclerosis and their haplogroup distribution.

INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) may be familial or sporadic, and twin studies have revealed that even sporadic forms have a significant genetic component. Variants in 55 nuclear genes have been associated with ALS and although mitochondrial dysfunction is observed in ALS, variants in mitochondrial genomes (mitogenomes) have not yet been tested for association with ALS. The aim of this study was to determine whether mitogenome variants are associated with ALS. METHODS: We conducted a genome-wide association study (GWAS) in mitogenomes of 1965 ALS patients and 2547 controls. RESULTS: We identified 51 mitogenome variants with p values <10-7, of which 13 had odds ratios (ORs) >1, in genes RNR1, ND1, CO1, CO3, ND5, ND6, and CYB, while 38 variants had OR <1 in genes RNR1, RNA2, ND1, ND2, CO2, ATP8, ATP6, CO3, ND3, ND4, ND5, ND6, and CYB. The frequencies of haplogroups H, U, and L, the most frequent in our ALS data set, were the same in different onset sites (bulbar, limb, spinal, and axial). Also, intra-haplogroup GWAS revealed unique ALS-associated variants in haplogroups L and U. DISCUSSION: Our study shows that mitogenome single nucleotide variants (SNVs) are associated with ALS and suggests that these SNVs could be included in routine genetic testing for ALS and that mitochondrial replacement therapy has the potential to serve as a basis for ALS treatment.

Influence of IL-ß, IL-1RN, and TNF-α variants on the risk of acetylsalicylic acid-induced upper gastrointestinal bleeding: a case-control study.

OBJECTIVE: Forgerini et al. investigated the role of seven genetic variants in the risk of upper gastrointestinal bleeding as an adverse drug reaction. In 289 participants (50 cases and 189 controls), the presence of seven variants in the IL-1ß, IL-1RN, and TNF-α genes was not associated with susceptibility to acetylsalicylic acid-induced upper gastrointestinal bleeding. The use of acetylsalicylic acid, even in low doses, may be associated with the onset of upper gastrointestinal bleeding as an idiosyncratic response. Considering the role of the genetic background in inter-individual responses to pharmacotherapy, we aimed to investigate the role of seven variants in the TNF-α, IL-ß, and IL-1RN genes in association with the risk of upper gastrointestinal bleeding in users of low-dose acetylsalicylic acid for the prevention of cardiovascular events. METHODS: A case-control study was conducted in a Brazilian hospital complex. The Case Group comprised patients diagnosed with upper gastrointestinal bleeding who were administered a low dose of acetylsalicylic acid (n=50). Two Control Groups were recruited: 1) low-dose acetylsalicylic acid users without gastrointestinal complaints and under the supervision of a cardiologist (n=50) and 2) healthy controls (n=189). Sociodemographic, clinical, pharmacotherapeutic, and lifestyle data were recorded through face-to-face interviews. Genomic DNA from all participants was genotyped for rs16944 and rs1143634 (IL-ß gene), rs4251961 (IL-1RN gene), and rs1799964, rs1799724, rs361525, and rs1800629 (TNF-α gene). RESULTS: No significant difference was noted in the genotypic frequencies of TNF-α, IL-ß, and IL-1RN variants between the Case and Control Groups of low-dose acetylsalicylic acid users (p>0.05). The frequency of rs1800629 genotypes (TNF-α gene) differed significantly between the Case Group and healthy controls (p=0.003). None of the evaluated variants were associated with a risk of upper gastrointestinal bleeding. CONCLUSION: This study aimed to explore pharmacogenomics biomarkers in low-dose acetylsalicylic acid users. Our data suggest that the presence of IL-1ß, IL-1RN, and TNF-α variants was not associated with an increased risk of upper gastrointestinal bleeding.

Genetic association of the BsmI variant of vitamin D receptor gene with risk of morbid obesity.

OBJECTIVE: The aim of this study was to evaluate the vitamin D receptor (VDR) BsmI variant in morbidly obese patients compared with healthy normal controls. METHODS: The study included 103 patients with morbid obesity and 120 healthy individuals serving as normal controls. The DNA samples obtained from blood were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The gender, age, smoking status, triglycerides, total cholesterol, insulin, mean body mass index, and frequency of allele and genotype of the BsmI variant in the VDR gene in morbidly obese patients were evaluated. RESULTS: The body mass index of the patients was 47.14 ± 7.19. The VDR B/B, B/b, and b/b genotype frequencies were 27.2% versus 28.3%; 54.4% versus 50%; and 18.4% versus 21.7% in the morbidly obese patients and the control group, respectively. There was no statistically significant difference between patients and control subjects in the genotype and allele distribution of the VDR BsmI variant (p>0.05). Both patients and control genotype frequencies are consistent with Hardy-Weinberg equilibrium. CONCLUSION: The BsmI variant in the VDR gene may not seem to predispose to morbid obesity in our study population. Further studies with a larger number of subjects are needed to make a more precise evaluation of this relationship.

The role of the Chitinase 3-Like 1 (CHI3L1) genes in the preeclampsia pathophysiology.

OBJECTIVE: The aim of this study was to investigate the relationship between Chitinase 3-Like 1 gene polymorphisms and the occurrence of preeclampsia in a selected cohort of pregnant women. METHODS: A total of 75 pregnant women participated in the study, 35 of whom were diagnosed with preeclampsia, while 40 served as healthy controls. The preeclamptic group was subdivided based on severity. Real-time polymerase chain reaction was employed to analyze the serum samples for variations in Chitinase 3-Like 1 gene polymorphisms. RESULTS: The rs880633 polymorphism was found to be significantly more frequent in the control group (80%) compared with the overall preeclamptic group (60%) (p<0.05). In the severity-based subgroups, rs880633 appeared in 57.1% of non-severe and 61.9% of severe preeclamptics. Contrarily, the heterozygous form of rs7515776 polymorphism showed a significantly higher prevalence in the preeclamptic cohort (p<0.05), without distinctions in severity subgroups. CONCLUSION: The study suggests that the rs880633 polymorphism may serve a protective role against the development of preeclampsia, whereas the rs7515776 polymorphism may be associated with an elevated risk. Further research is warranted to elucidate the clinical implications of these findings.

NAMPT gene rs2058539 variant is a risk factor for nonalcoholic fatty liver disease.

OBJECTIVE: Nonalcoholic fatty liver disease is a chronic liver disease and a growing global epidemic. The aim of this study was to investigate the association between a visfatin gene (NAMPT) variant and nonalcoholic fatty liver disease, owing to the connection between this disease and insulin resistance, obesity, inflammation, and oxidative stress, and the role of visfatin in these metabolic disorders. METHODS: In the present case-control study, we enrolled 312 genetically unrelated individuals, including 154 patients with biopsy-proven nonalcoholic fatty liver disease and 158 controls. The rs2058539 polymorphism of NAMPT gene was genotyped using the PCR-RFLP method. RESULTS: Genotype and allele distributions of NAMPT gene rs2058539 polymorphism conformed to the Hardy-Weinberg equilibrium both in the case and control groups (p>0.05). The distribution of NAMPT rs2058539 genotypes and alleles differed significantly between the cases with nonalcoholic fatty liver disease and controls. The "CC" genotype of the NAMPT rs2058539 compared with "AA" genotype was associated with a 2.5-fold increased risk of nonalcoholic fatty liver disease after adjustment for confounding factors [p=0.034; odds ratio (OR)=2.52, 95% confidence interval (CI)=1.36-4.37]. Moreover, the NAMPT rs2058539 "C" allele was significantly overrepresented in the nonalcoholic fatty liver disease patients than controls (p=0.022; OR=1.77, 95%CI=1.14-2.31). CONCLUSION: Our findings indicated for the first time that the NAMPT rs2058539 "CC" genotype is a marker of increased nonalcoholic fatty liver disease susceptibility; however, it needs to be supported by further investigations in other populations.

The rs1862513 promoter variant of resistin gene influences susceptibility to nonalcoholic fatty liver disease.

OBJECTIVES: Nonalcoholic fatty liver disease is the term used for a range of conditions in which fat builds up in the liver and exceeds 5% of hepatocytes without inordinate alcohol intake or other causes of lipid accumulation. Regarding the fact that insulin resistance and obesity play key roles in the pathogenesis of nonalcoholic fatty liver disease, as well as the connection between resistin and these metabolic diseases, the association between nonalcoholic fatty liver disease and a resistin gene (RETN) polymorphism was examined. METHODS: In this genetic case-control association study, 150 biopsy-proven nonalcoholic fatty liver disease patients and 154 controls were enrolled and genotyped for the RETN rs1862513 (-420C>G) gene polymorphism using PCR-RFLP method. RESULTS: The -420C>G genotype frequency distributions in both groups were consistent with Hardy-Weinberg equilibrium (HWE; p>0.05). The carriers of the RETN -420C>G "CC" genotype compared with the "GG" genotype occurred less frequently in the cases with nonalcoholic fatty liver disease than in the controls, and the difference remained significant even after adjustment for confounding factors (p=0.030; OR=0.47, 95%CI=0.36-0.93). Interestingly, the RETN -420C>G "C" allele was also associated with a decreased risk for nonalcoholic fatty liver disease too (p=0.042; OR=0.72, 95%CI=0.53-0.95). CONCLUSION: We found for the first time an association between biopsy-proven nonalcoholic fatty liver disease and RETN -420C>G promoter polymorphism. The carriers of the RETN -420C>G "CC" genotype had a 53% decreased risk for nonalcoholic fatty liver disease. Our findings, however, need to be corroborated by further studies.

The association of CYP11A1 gene polymorphisms with the polycystic ovary syndrome patients.

OBJECTIVE: The objective of this study was to investigate the allele frequencies of polymorphisms in genes CYP11A1 rs4886595 and CYP11A1 rs4887139 that are responsible for the steroidogenesis mechanism in polycystic ovary syndrome patients and control females. METHODS: Samples were obtained from the Department of Obstetrics and Gynecology in the Near East University Hospital from September 2019 to December 2019. Only the nonobese patients between the ages of 18-40 years were included in this study following informed consent. Obese patients and patients more than 40 years of age were excluded from the study. Nonobese women and normal ovulation were included in the control group. DNA was isolated from blood samples. Real-time polymerase chain reaction (PCR) was used to analyze single nucleotide polymorphisms (SNPs) in various genes linked to polycystic ovary syndrome. The studies were carried out using the samples obtained from 120 women, of whom 55 were nonobese and had normal ovulation, and 65 were polycystic ovary syndrome patients. The allelic frequencies of SNPs in genes linked to polycystic ovary syndrome were calculated using real-time PCR outcomes. RESULTS: The variation of the CYP11A1 rs4887139 G>A did not show any significance, while the variation of CYP11A1 rs4886595 C>A showed significant differences between the patient and the control groups (p=0.01), respectively. CONCLUSION: Future research ought to focus on elucidating the susceptible causes of polycystic ovary syndrome with a wide range of SNPs and more sample size. The genome-wide association studies in polycystic ovary syndrome patients of different origin will be important to identify candidate genes as well as proteins that are implied in polycystic ovary syndrome risk.

IL18 rs360717 and rs187238 genetic variants are associated with migraine diagnosis.

BACKGROUND: Migraine is a genetically determined disorder that predisposes to recurrent episodes of headache. Interleukin (IL)-18 is a pro-inflammatory cytokine that seems to play a role in migraine pathophysiology, and its genetic variants could potentially impact susceptibility to migraine. OBJECTIVE: To investigate the association between IL18 rs360717 and rs187238 genetic variants with migraine diagnosis and its clinical characteristics. METHODS: A case-control study was conducted with 152 people with migraine and 155 healthy controls, matched by sex, age, ethnicity, and body mass index. Clinical characteristics of migraine, as well as validated questionnaires regarding disability and impact of migraine, presence of allodynia, anxiety, depression, and hyperacusis were collected. Genotyping for IL18 rs360717 and rs187238 variants was performed using real-time polymerase chain reaction (qPCR) and TaqMan™ method. RESULTS: The IL18 rs360717A and rs187238G alleles were associated with increased chance of being diagnosed with migraine (OR = 1.53, 95%CI 1.05-2.24, p = 0.028 and OR = 1.46, 95%CI 1.00-2.14, p = 0.049, respectively). In the dominant model, the rs360717GA + AA genotypes were also associated with a higher chance of migraine than the GG genotype (OR = 1.69, 95%CI 1.05-2.73, p = 0.030). In women, in addition to the previous associations, there was also an effect of the variants on the chance of migraine in the codominant models and dominant models. Furthermore, among women, there was an influence on the prevalence of postdrome perception with rs360717GA + AA (OR = 3.04, 95%CI 1.10-8.42, p = 0.032) and rs187238CG + GG (OR = 2.97, 95%CI 1.08-8.21, p = 0.035). CONCLUSION: IL18 rs360717 and rs187238 variants were associated with migraine diagnosis and postdrome symptoms, especially in women. SIGNIFICANCE: This study has demonstrated that IL18 rs360717 and rs187238 variants play a role in migraine, influencing the chance of being diagnosed with migraine, particularly among women. There are prospects that IL18 variants could be considered potential genetic biomarkers for migraine.

Autoimmunity-related LINC01934 and AP002954.4 lncRNA polymorphisms may be effective in pediatric celiac disease: a case-control study.

OBJECTIVE: Various studies have reported that certain long non-coding RNA levels are unusually low in the intestines of celiac disease patients, suggesting that this may be associated with the inflammation observed in celiac disease. Despite these studies, the research aimed at uncovering the potential role of long non-coding RNAs in the pathogenesis of autoimmune diseases like celiac disease remains insufficient. Therefore, in this study, we plan to assess long non-coding RNA polymorphisms associated with autoimmunity in children diagnosed with celiac disease according to the European Society for Paediatric Gastroenterology Hepatology and Nutrition criteria. METHODS: DNA was isolated from paraffin tissue samples of 88 pediatric celiac disease patients and 74 healthy pediatric individuals. Single-nucleotide polymorphism genotyping of five long non-coding RNA polymorphisms associated with autoimmunity (LINC01934-rs1018326, IL18RAP-rs917997, AP002954.4-rs10892258, UQCRC2P1-rs6441961, and HCG14 rs3135316) was conducted using the TaqMan single-nucleotide polymorphism genotyping assays with the LightCycler 480. RESULTS: In our study, the genotypic and allelic frequency distribution of LINC01934-rs1018326 and AP002954.4-rs10892258 polymorphisms was found to be statistically significant in the comparison between the two groups (p<0.05). According to the multiple genetic model analyses, the LINC01934-rs1018326 polymorphism was observed to confer a 1.14-fold risk in the recessive model and a 1.2-fold risk in the additive model for pediatric celiac disease. Similarly, the AP002954.4-rs10892258 polymorphism was found to pose a 1.40-fold risk in the dominant model and a 1.7-fold risk in the additive model. CONCLUSION: Our study results draw attention to the LINC01934-rs1018326 and AP002954.4-rs10892258 polymorphisms in celiac disease and suggest that these polymorphisms may be associated with inflammation in autoimmune diseases like celiac disease.

IFITM3 rs12252 polymorphism association with COVID-19 severity and mortality in a Brazilian sample: an update and a meta-analysis.

This study investigated the association between the IFITM3 rs12252 polymorphism and the severity and mortality of COVID-19 in hospitalized Brazilian patients. A total of 102 COVID-19 patients were included, and the outcomes of interest were defined as death and the need for mechanical ventilation. Genotypes were assessed using Taqman probes. No significant associations were found between the rs12252 polymorphism and COVID-19 outcomes in the original sample, both for death and the need for mechanical ventilation. A meta-analysis, incorporating previous studies that used death as a severity indicator, revealed no association in the allelic and C-recessive models. However, due to the rarity of the T allele and its absence in the sample, further replication studies in larger and more diverse populations are needed to clarify the role of rs12252 in COVID-19 prognosis.

Genetic variants in miR-146a and miR-196a2 in endometriosis: a Brazilian study.

OBJECTIVE: The aim of this study was to determine the allelic and genotypic frequencies of the polymorphisms, rs2910164 miR-146a and rs11614913 miR-196a2, by investigating their association with endometriosis. METHODS: This is a case-control study performed with approximately 120 women. The polymorphisms were determined by real-time polymerase chain reaction. For the statistical analysis, the chi-square and logistic regression tests were used. RESULTS: There were no significant differences in the genotype and allele frequencies of rs2910164 and rs11614913 between cases and controls. The frequencies in both polymorphisms are in accordance with Hardy-Weinberg equilibrium regarding miR-146a (patients: χ2=1.64, p=0.20; controls: χ2=0.25, p=0.62) and miR-196a2 (patients: χ2=0.58, p=0.44; controls: χ2=2.78, p=0.10). No relationship was observed between rs2910164 and rs11614913 and endometriosis in the inheritance models analyzed. CONCLUSION: In this study, our results show that the studied polymorphisms are not implicated in the development of endometriosis.

MTHFR 677C>T and 1298A>C Variants in Mothers of Infants with Down Syndrome from Western Mexico.

Background: Several studies in mothers of infants with Down syndrome (DS) (MoIDS) have suggested that the 677C>T and 1298A>C variants of the 5,10-methylentetrahydrofolate reductase (MTHFR) gene can increase the risk of having a child with DS. Aim: This study aimed to evaluate the MTHFR 677C>T and 1298A>C variants as potential maternal risk factors for DS. Materials and Methods: Using TaqMan allelic discrimination assay, we genotyped 95 MoIDS and 164 control mothers from western Mexico. Data were analyzed using logistic regression analysis. Results: We found that MoIDS had a significantly higher risk for the MTHFR 677TT genotype (adjusted odds ratio [aOR] = 3.4, 95% confidence interval [95% CI]: 1.1-10.6), and the MTHFR 677T allele (aOR = 1.5, 95% CI: 1.0-2.3), particularly in MoIDS <35 years of age. Conclusions: Our findings indicate that the presence of the 677TT genotype and 677T allele of the MTHFR 677C>T variant are maternal risk factors for DS in Mexican MoIDS.

Exploring the role of the WNT5A rs566926 polymorphism and its interactions in non-syndromic orofacial cleft: a multicenter study in Brazil.

BACKGROUND: Associations between the WNT5A rs566926 variant and non-syndromic orofacial cleft (NSOC) have been reported in different populations. OBJECTIVE: This study aimed to investigate the role of the rs566926 single nucleotide polymorphism (SNP) in WNT5A and its interactions with SNPs in BMP4, FGFR1, GREM1, MMP2, and WNT3 in the occurrence of NSOC in a Brazilian population. METHODOLOGY: A case-control genetic association study was carried out involving participants from four regions of Brazil, totaling 801 patients with non-syndromic cleft lip with or without cleft palate (NSCL±P), 273 patients with cleft palate only (NSCPO), and 881 health volunteers without any congenital condition (control). Applying TaqMan allelic discrimination assays, we evaluated WNT5A rs566926 in an ancestry-structured multiple logistic regression analysis, considering sex and genomic ancestry as covariates. Interactions between rs566926 and variants in genes involved in the WNT5A signaling pathway (BMP4, FGFR1, GREM1, MMP2, and WNT3) were also explored. RESULTS: WNT5A rs566926 was significantly associated with an increased risk of NSCL±P, particularly due to a strong association with non-syndromic cleft lip only (NSCLO), in which the C allele increased the risk by 32% (OR: 1.32, 95% CI: 1.04-1.67, p=0.01). According to the proportions of European and African genomic ancestry, the association of rs566926 reached significant levels only in patients with European ancestry. Multiple interactions were detected between WNT5A rs566926 and BMP4 rs2071047, GREM1 rs16969681 and rs16969862, and FGFR1 rs7829058. CONCLUSION: The WNT5A rs566926 polymorphism was associated with NSCL±P, particularly in individuals with NSCLO and high European ancestry. Epistatic interactions involving WNT5A rs566926 and variants in BMP4, GREM1, and FGFR1 may contribute to the risk of NSCL±P in the Brazilian population.

Influence of TMX2-CTNND1 polymorphism on cortical thickness in schizophrenia patients and unaffected siblings: an exploratory study based on target region sequencing.

OBJECTIVE: The advancement of neuroimaging and genetic research has revealed the presence of morphological abnormalities and numerous risk genes, along with their associations. We aimed to estimate magnetic resonance imaging-derived cortical thickness across multiple brain regions. METHODS: The cortical thickness of 129 schizophrenia patients, 42 of their unaffected siblings, and 112 healthy controls was measured and the candidate genes were sequenced. Comparisons were made of cortical thickness (including 68 regions of the Desikan-Killiany Atlas) and genetic variants (in 108 risk genes for schizophrenia) among the three groups, and correlation analyses were performed regarding cortical thickness, clinical symptoms, cognitive tests (such as the N-back task and the logical memory test), and genetic variants. RESULTS: Schizophrenia patients had significantly thinner bilateral frontal, temporal, and parietal gyri than healthy controls and unaffected siblings. Association analyses in target genes showed that four single nucleotide variants (SNVs) were significantly associated with schizophrenia, including thioredoxin-related transmembrane protein 2-catenin, cadherin-associated protein, delta 1 (SNV20673) (positive false discovery rate [PFDR] = 0.008) and centromere protein M (rs35542507, rs41277477, rs73165153) (PFDR = 0.030). Additionally, cortical thickness in the right pars triangularis was lower in carriers of the SNV20673 variant than in non-carriers (PFDR = 0.048). Finally, a positive correlation was found between right pars triangularis cortical thickness and logical memory in schizophrenia patients (r = 0.199, p = 0.032). CONCLUSIONS: This study identified regional morphological abnormalities in schizophrenia, including the right homologue of Broca's area, which was associated with a risk variant that affected delta-1 catenin and logical memory. These findings suggest a potential association between candidate gene loci, cortical thickness, and schizophrenia.

The first genome-wide association study in the Argentinian and Chilean populations identifies shared genetics with Europeans in Alzheimer's disease.

INTRODUCTION: Genome-wide association studies (GWAS) are fundamental for identifying loci associated with diseases. However, they require replication in other ethnicities. METHODS: We performed GWAS on sporadic Alzheimer's disease (AD) including 539 patients and 854 controls from Argentina and Chile. We combined our results with those from the European Alzheimer and Dementia Biobank (EADB) in a meta-analysis and tested their genetic risk score (GRS) performance in this admixed population. RESULTS: We detected apolipoprotein E ε4 as the single genome-wide significant signal (odds ratio  = 2.93 [2.37-3.63], P = 2.6 × 10-23 ). The meta-analysis with EADB summary statistics revealed four new loci reaching GWAS significance. Functional annotations of these loci implicated endosome/lysosomal function. Finally, the AD-GRS presented a similar performance in these populations, despite the score diminished when the Native American ancestry rose. DISCUSSION: We report the first GWAS on AD in a population from South America. It shows shared genetics modulating AD risk between the European and these admixed populations. HIGHLIGHTS: This is the first genome-wide association study on Alzheimer's disease (AD) in a population sample from Argentina and Chile. Trans-ethnic meta-analysis reveals four new loci involving lysosomal function in AD. This is the first independent replication for TREM2L, IGH-gene-cluster, and ADAM17 loci. A genetic risk score (GRS) developed in Europeans performed well in this population. The higher the Native American ancestry the lower the GRS values.

Study on the correlation between gene polymorphisms of adiponectin and resistin levels and abdominal aortic aneurysm.

OBJECTIVES: Abdominal Aortic Aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. This study aimed to examine the potential association of the +276G/T and -420C>G polymorphisms in the resistin gene with AAA susceptibility and progression. METHOD: We performed a retrospective study involving AAA patients and healthy controls, assessing the distribution of the +276G/T and -420C>G genotypes in both groups. Hardy-Weinberg equilibrium was assessed for both polymorphisms. Logistic regression was used to explore the influence of these genotypes on AAA occurrence and progression, adjusting for relevant confounders. RESULTS: The distribution of +276G/T polymorphism did not significantly differ between AAA patients and controls. Conversely, a significant difference was observed in the genotype distribution of -420C>G polymorphism between the two groups. The CC genotype and CC/CG genotypes of -420C>G polymorphism were found to be associated with an increased risk and progression of AAA. CONCLUSIONS: The -420C>G polymorphism, particularly the CC genotype and CC/CG genotypes, might play a substantial role in AAA susceptibility and progression. The present findings underscore the need for further investigations to confirm these associations and fully elucidate the role of the resistin gene in AAA.

Efecto del sedentarismo sobre la interacción entre el gen FTO y niveles de adiposidad en adultos chilenos - Resultados del Estudio GENADIO / Effect of Sedentary behaviors on the Interaction Between the FTO Gene and Adiposity Levels in Chilean Adults - Results from the GENADIO Study

ANTECEDENTES: Tanto el gen FTO (Fat-mass and obesity-associated-gene) y el tiempo sedente se asocian a obesidad, sin embargo, se desconoce si el tiempo sedente puede modificar la predisposición genética a la obesidad. Por ende, el objetivo de este estudio fue investigar si la asociación entre el polimorfismo rs9939609 del gen FTO y marcadores de adiposidad podrían ser modificados por el tiempo sedente. MÉTODOS: Este estudio de corte transversal incluye a 409 participantes del estudio GENADIO. Los marcadores de adiposidad estudiados fueron peso corporal, índice de masa corporal (IMC), perímetro de cintura (PC) y porcentaje masa grasa. El tiempo sedente se determinó mediante acelerometría de movimiento. La interacción entre el gen FTO (rs9939609) y el tiempo sedente sobre los marcadores de adiposidad se determinó mediante análisis de regresión múltiple. RESULTADOS: Tanto la variante de riesgo del gen FTO como el tiempo sedente se asociaron a mayor peso corporal, IMC, PC y masa grasa. Sin embargo, la asociación entre tiempo sedente y marcadores de adiposidad fue mayor en personas portadoras del alelo de riesgo del gen FTO. Por cada 1 hora de incremento en tiempo sedente, el peso corporal incrementa en 1,36 kg ([95% IC: 0,27; 2,46], p = 0,015) y 2,95 kg ([95% IC: 1,24; 4,65], p = 0,001) en personas con la variante protectora (TT) versus aquellos con la variante de riesgo (AA), respectivamente. Resultados similares se encontraron para (PC). CONCLUSIÓN: La asociación entre la variante de riesgo de FTO y mayor nivel de adiposidad es más acentuada en individuos que presentan mayores niveles de sedentarismo.

BACKGROUND: The Fat-mass and obesity-associated-gene (FTO gene) and sedentary behavior time are associated with obesity. However, whether sedentary behavior time can modify the genetic predisposition to obesity in the Chilean population is unknown. Therefore, this study investigated the association between sedentary behavior, adiposity markers, and the FTO gene. METHODS: This cross-sectional study included 409 participants from the Genes, Environment, Diabetes, and Obesity (GENADIO) study. Adiposity markers studied included body weight, body mass index (BMI), waist circumference (WC), and fat mass. Sedentary behaviors were measured using accelerometers. Using multiple regression, we evaluated the interaction between sedentary behaviors and the FTO gene (rs9939609) on adiposity markers. RESULTS: Sedentary behaviors and the FTO genotype were positively associated with higher body weight, BMI, WC, and fat mass. However, the association between time of sedentary behavior and adiposity markers was higher in carriers of the risk variant for the FTO gene. For each hour of increment in sedentary behaviors, body weight increases by 1.36 kg ([95% CI: 0.27; 2.46], p = 0.015) and 2.95 kg ([95%CI: 1.24; 4.65], p = 0.001) in non-risk carriers (TT) versus risk carriers (AA), respectively. We observed similar results for WC, BMI, and body fat, but the interaction was significant only for WC. CONCLUSION: The association between sedentary behaviors and adiposity markers, especially body weight and WC, is higher in individuals who carry the risk variant of the FTO gene.

TPH2-703 G/T polymorphism is associated with stress, depression, and psychosocial symptoms in mentally healthy Mexicans.

Tryptophan hydroxylase (TPH) catalyzes the rate-limiting step of serotonin synthesis. TPH2 is the brain-specific isoform of this enzyme, and genetic variations in the TPH2 gene have been shown to impact its transcription and enzymatic activity and are associated with mood disorders. In this study we focused on the rs4570625 (-703G/T) single nucleotide polymorphism of TPH2 gene. By using conventional polymerase chain reaction (PCR), we examined the effect of this polymorphism on stress, anxiety, and depression symptoms as well as quality of life, evaluated based on the Holmes-Rahe Inventory, the Beck Anxiety Inventory, the Beck Depression Inventory, and the World Health Organization Quality of Life - Short Version, respectively. We found that individuals with the homozygous recessive T/T genotype had lower stress and depression scores. In addition, the quality of life in the psychological health domain was better in males with the T/T genotype. These results suggest that T/T genotype could decrease the susceptibility to developing stress and depression in the Mexican population without a diagnosis for an emotional disorder.